Method of treatment for decreasing mortality resulting from congestive heart failure

ABSTRACT

A method of treatment using a compound of Formula I: ##STR1## wherein: R 1  is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroyl selected from benzoyl and naphthoyl; 
     R 2  is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl and phenylpropyl; 
     R 3  is hydrogen or lower alkyl of up to 6 carbon atoms; 
     R 4  is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen, R 4  together with R 5  can represent --CH 2  --O--; 
     X is a valency bond, --CH 2 , oxygen or sulfur; 
     Ar is selected from phenyl, naphthyl, indanyl and tetrahydronaphthyl; 
     R 5  and R 6  are individually selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a --CONH 2  -- group, lower alkoxy of up to 6 carbon atoms, benzyloxy, lower alkylthio of up to 6 carbon atoms, lower alkysulphinyl of up to 6 carbon atoms and lower alkylsulphonyl of up to 6 carbon atoms; or 
     R 5  and R 6  together represent methylenedioxy; 
     or a pharmaceutically acceptable salt thereof, alone or in conjunction with one or more other therapeutic agents, said agents being selected from the group consisting of ACE inhibitors, diuretics, and digoxin for decreasing mortality resulting from congestive heart failure (CHF) in mammals, particularly humans.

FIELD OF THE INVENTION

The present invention relates to a new method of treatment usingcompounds which are dual non-selective β-adrenoceptor and α₁-adrenoceptor antagonists, in particular thecarbazolyl-(4)-oxypropanolamine compounds of Formula I, preferablycarvedilol, for decreasing the mortality of patients suffering fromcongestive heart failure (CHF). The invention also relates to a methodof treatment using compounds which are dual non-selective β-adrenoceptorand α₁ -adrenoceptor antagonists, in particular thecarbazolyl-(4)-oxypropanolamine compounds of Formula I, preferablycarvedilol, in conjunction with one or more other therapeutic agents,said agents being selected from the group consisting of angiotensinconverting enzyme (ACE) inhibitors, diuretics, and digoxin, fordecreasing the mortality of patients suffering from CHF.

BACKGROUND OF THE INVENTION

Congestive heart failure occurs as a result of impaired pumpingcapability of the heart and is associated with abnormal retention ofwater and sodium. Traditionally, treatment of chronic mild failure hasincluded limitation of physical activity, restriction of salt intake,and the use of a diuretic. If these measures are not sufficient,digoxin, which is an agent that increases the force of mycardialcontraction, is typically added to the treatment regiment. Subsequently,angiotensin converting enzyme inhibitors, which are compounds thatprevent the conversion of angiotensin I into the pressor-activeangiotensin II, are prescribed for chronic treatment of congestive heartfailure, in conjunction with a diuretic, digoxin, or both.

Congestive heart failure is a condition that is associated withactivation of both the renin-angiotensin system (RAS) and thesympathetic nervous system (SNS). Modulation of the RAS by angiotensinconverting enzyme inhibitors has been shown to improve the symptomsassociated with CHF. Sharpe, D. N., Murphy, J., Coxon, R. & Hannan S. F.(1984) Circulation, 70, 271-278. However, ACE inhibitors appear to havelittle effect on the enhanced SNS in CHF. Cohn, J. N., Johnson, G. &Ziesche, S., (1991) N. Engl. J. Med., 325, 293-302 and Francis, G. S.,Rector, T. S. & Cohn, J. N. (1988) Am. Heart J., 116, 1464-1468.Therefore, there is a need for an agent that would be effective inblocking the activation of the SNS in CHF patients.

Also, congestive heart failure is a well-known cardiac disorder whichresults in an annual mortality in excess of 50 percent. Applefeld, M.M., (1986) Am. J. Med., 80, Suppl. 2B, 73-77. Therefore, therapeuticagents that would decrease the mortality resulting from CHF in patientssuffering therefrom are highly desirable.

SUMMARY OF THE INVENTION

The present invention provides a new method of treatment usingpharmaceutical compounds which are dual non-selective β-adrenoceptor andα₁ -adrenoceptor antagonists and, in particular, thecarbazolyl-(4)-oxypropanolamine compounds of Formula I, alone or inconjunction with one or more other therapeutic agents, said agents beingselected from the group consisting of ACE inhibitors, diuretics, anddigoxin, as therapeutics for decreasing mortality resulting fromcongestive heart failure in mammals, particularly humans. In particular,the present invention preferably provides a method of treatment, aloneor in conjunction with one or more other therapeutic agents, said agentsbeing selected from the group consisting of ACE inhibitors, diuretics,and digoxin, for the compound of Formula I wherein R₁ is --H, R₂ is --H,R₃ is --H, R₄ is --H, X is O, Ar is phenyl, R₅ is ortho --OCH₃, and R₆is --H, said compound being better known as carvedilol, which is(1-(carbazol-4-yloxy-3- 2-(o-methoxyphenoxy)ethyl!amino!-2-propanol), ora pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

U.S. Pat. No. 4,503,067 discloses carbazolyl-(4)-oxypropanolaminecompounds of Formula I: ##STR2## wherein: R₁ is hydrogen, lower alkanoylof up to 6 carbon atoms or aroyl selected from benzoyl and naphthoyl;

R₂ is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkylselected from benzyl, phenylethyl and phenylpropyl;

R₃ is hydrogen or lower alkyl of up to 6 carbon atoms;

R₄ is hydrogen or lower alkyl of up to 6 carbon atoms, or when X isoxygen, R₄ together with R₅ can represent --CH₂ --O--;

X is a valency bond, --CH₂, oxygen or sulfur;

Ar is selected from phenyl, naphthyl, indanyl and tetrahydronaphthyl;

R₅ and R₆ are individually selected from hydrogen, fluorine, chlorine,bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a --CONH₂ --group, lower alkoxy of up to 6 carbon atoms, benzyloxy, lower alkylthioof up to 6 carbon atoms, lower alkysulphinyl of up to 6 carbon atoms andlower alkylsulphonyl of up to 6 carbon atoms; or

R₅ and R₆ together represent methylenedioxy;

and pharmaceutically acceptable salts thereof.

This patent further discloses a compound of Formula I, better known ascarvedilol, which is (1-(carbazol-4-yloxy-3-2-(o-methoxyphenoxy)ethyl!amino!-2-propanol), having the structure shownin Formula II: ##STR3##

Formula I compounds, of which carvedilol is exemplary, are novelmultiple action drugs useful in the treatment of mild to moderatehypertension. Carvedilol is known to be both a competitive non-selectiveβ-adrenoceptor antagonist and a vasodilator, and is also a calciumchannel antagonist at higher concentrations. The vasodilatory actions ofcarvedilol result primarily from α₁ -adrenoceptor blockade, whereas theβ-adrenoceptor blocking activity of the drug prevents reflex tachycardiawhen used in the treatment of hypertension. These multiple actions ofcarvedilol are responsible for the antihypertensive efficacy of the drugin animals, particularly in humans. See Willette, R. N., Sauermelch, C.F. & Ruffolo, R. R., Jr. (1990) Eur. J. Pharmacol., 176,237-240;Nichols, A. J., Gellai, M. & Ruffolo, R. R., Jr. (1991) Fundam. Clin.Pharmacol., 5, 25-38; Ruffolo, R. R., Jr., Gellai, M., Hieble, J. P.,Willette, R. N. & Nichols, A. J. (1990) Eur. J. Clin. Pharmacol., 38,S82-S88; Ruffolo, R. R., Jr., Boyle, D. A., Venuti, R. P. & Lukas, M. A.(1991) Drugs of Today, 27, 465-492; and Yue, T.-L., Cheng, H., Lysko, P.G., Mckenna, P. J., Feuerstein, R., Gu, J., Lysko, K. A., Davis, L. L. &Feuerstein, G. (1992) J. Pharmacol. Exp. Ther., 263,92-98.

The antihypertensive action of carvedilol is mediated primarily bydecreasing total peripheral vascular resistance without causing theconcomitant reflex changes in heart rate commonly associated with otherantihypertensive agents. Willette, R. N., et al. supra; Nichols, A. J.,et al. supra; Ruffolo, R. R., Jr., Gellai, M., Hieble, J. P., Willette,R. N. & Nichols, A. J. (1990) Eur. J. Clin. Pharmacol., 38, S82-S88..Carvedilol also markedly reduces infarct size in rat, canine and porcinemodels of acute myocardial infarction, Ruffolo, R. R., Jr., et al.,Drugs of Today, supra, possibly as a consequence of its antioxidantaction in attenuating oxygen free radical-initiated lipid peroxidation.Yue, T.-L., et al. supra.

Recently, it has been discovered in clinical studies that pharmaceuticalcompounds which are dual non-selective β-adrenoceptor and α₁-adrenoceptor antagonists, in particular the compounds of Formula I,preferably carvedilol, alone or in conjunction with conventional agents,said agents being ACE inhibitors, diuretics, and digoxin, are effectivetherapeutic agents for treating CHF. The use of agents, such ascarvedilol in treating CHF is surprising, since, in general, β-blockersare contraindicated in patients suffering from heart failure, becauseβ-blockers are known to have undesirable cardiodepressive effects. Themost surprising observation from the studies in which the instantcompounds were used to treat CHF is that said compounds, in particularcarvedilol, are able to decrease the mortality resulting from CHF inhumans by about 67 percent. Furthermore, this result is present acrossall classifications of CHF and both etiologies (eschemic andnon-eschemic). This result is surprising since two recent mortalitystudies using the β-blockers metoprolol (Waagstein, et al., (1993)Lancet, 342, 1441-1446) and bisoprolol (CIBIS investigators andcommittees, (1994) Circulation, 90, 1765-1773) in the treatment of CHFshowed no difference in mortality between drug-treated patients andplacebo-treated patients.

According to the method of treatment of the present invention, thedesirable therapeutic effect of the compounds of Formula I, particularlycarvedilol, may be augmented by using any one of said compounds, or anypharmaceutically acceptable salt of said compounds, in conjunction withACE inhibitors, diuretics, and digoxin, which are effective therapeuticagents for the treatment of CHF. In particular, the preferred ACEinhibitors of the present invention are selected from the groupconsisting of captopril, lisinopril, and enalapril, or anypharmaceutically acceptable salts thereof and the preferred diuretics ofthe present invention are hydrochlorothiazide or furosemide, or anypharmaceutically acceptable salts thereof. The desireable therapeuticbenefits of the compounds of Formula I, particularly carvedilol, areadditive with those of such ACE inhibitors, or diuretics, or digoxinwhen administered in combination therewith. Captopril is commerciallyavailable from E. R. Squibb & Sons, Inc. Lisinopril, enalapril andhydrochloro-thiazide are commercially available from Merck & Co.Furosemide is commercially available from Hoechst-RousselPharmaceuticals, Inc. Digoxin is commercially available from BurroughsWellcome Co.

Compounds of Formula I may be conveniently prepared as described in U.S.Pat. No. 4,503,067. Carvedilol is commercially available from SmithKlineBeecham Corporation and Boehringer Mannheim GmbH (Germany).

Pharmaceutical compositions of the compounds of Formula I, includingcarvedilol, alone or in combination with ACE inhibitors, or diuretics,or digoxin may be administered to patients according to the presentinvention in any medically acceptable manner, preferably orally. Forparenteral administration, the pharmaceutical composition will be in theform of a sterile injectable liquid stored in a suitable container suchas an ampoule, or in the form of an aqueous or nonaqueous liquidsuspension. The nature and composition of the pharmaceutical carrier,diluent or excipient will, of course, depend on the intended route ofadministration, for example whether by intravenous or intramuscularinjection

Pharmaceutical compositions of the compounds of Formula I for useaccording to the present invention may be formulated as solutions orlyophilized powders for parenteral administration. Powders may bereconstituted by addition of a suitable diluent or otherpharmaceutically acceptable carrier prior to use. The liquid formulationis generally a buffered, isotonic, aqueous solution. Examples ofsuitable diluents are normal isotonic saline solution, standard 5%dextrose in water or buffered sodium or ammonium acetate solution. Suchformulation is especially suitable for parenteral administration, butmay also be used for oral administration or contained in a metered doseinhaler or nebulizer for insufflation. It may be desirable to addexcipients such as ethanol, polyvinyl-pyrrolidone, gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium chloride orsodium citrate.

Alternatively, these compounds may be encapsulated, tableted or preparedin a emulsion or syrup for oral administration. Pharmaceuticallyacceptable solid or liquid carriers may be added to enhance or stabilizethe composition, or to facilitate preparation of the composition. Liquidcarriers include syrup, peanut oil, olive oil, glycerin, saline,ethanol, and water. Solid carriers include starch, lactose, calciumsulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc,pectin, acacia, agar or gelatin. The carrier may also include asustained release material such as glyceryl monostearate or glyceryldistearate, alone or with a wax. The amount of solid carrier varies but,preferably, will be between about 20 mg to about 1 g per dosage unit.The pharmaceutical preparations are made following the conventionaltechniques of pharmacy involving milling, mixing, granulating, andcompressing, when necessary, for tablet forms; or milling, mixing andfilling for hard gelatin capsule forms. When a liquid carrier is used,the preparation will be in the form of a syrup, elixir, emulsion or anaqueous or non-aqueous suspension. Such a liquid formulation may beadministered directly p.o. or filled into a soft gelatin capsule.

Dosing in humans for the treatment of disease according to the presentinvention should not exceed a dosage range of from about 3.125 to about50 mg of the compounds of Formula I, particularly carvedilol, preferablygiven twice daily. As one of ordinary skill in the art will readilycomprehend, the patient should be started on a low dosage regimen of thedesired compound of Formula I, particularly carvedilol, and moniteredfor well-known symptoms of intolerance, e.g., fainting, to suchcompound. Once the patient is found to tolerate such compound, thepatient should be brought slowly and incrementally up to the maintenancedose. The preferred course of treatment is to start the patient on adosage regimen of either 3.125 or 6.25 mg, preferably given twice daily,for two weeks. The choice of initial dosage most appropriate for theparticular patient is determined by the practitioner using well-knownmedical principles, including, but not limited to, body weight. In theevent that the patient exhibits medically acceptable tolerance of thecompound for two weeks, the dosage is doubled at the end of the twoweeks and the patient is maintained at the new, higher dosage for twomore weeks, and observed for signs of intolerance. This course iscontinued until the patient is brought to a maintenance dose. Thepreferred maintenance dose is 25 mg, preferably given twice daily, forpatients having a body weight of up to 85 kg. For patients having a bodyweight of over 85 kg, the maintenance dose is between about 25 mg andabout 50 mg, preferably given twice daily; preferably about 50 mg,preferably given twice daily.

Dosing in humans for the treatment of disease according to the presentinvention includes the combination of compounds of Formula I withconventional agents. For example, the usual adult dosage ofhydrochlorothiazide is 25-100 mg daily as a single dose or divided dose.The recommended starting dose for enalapril is 2.5 mg administered onceor twice daily. The usual therapeutic dosing range for enalapril is 5-20mg daily, given as a single dose or two divided doses. For most patientsthe usual initial daily dosage of captopril is 25 mg tid, with mostpatients having a satisfactory clinical improvement at 50 or 100 mg tid.

It will be appreciated that the actual preferred dosages of thecompounds being used in the compositions of this invention will varyaccording to the particular composition formulated, the mode ofadministration, the particular site of administration and the host beingtreated.

No unacceptable toxicological effects are expected when the compounds ofFormula I, including the compound of Formula II, are used according tothe present invention.

The example which follows is intended in no way to limit the scope ofthis invention, but is provided to illustrate how to use the compoundsof this invention. Many other embodiments will be readily apparent tothose skilled in the art.

EXPERIMENTAL Mortality Studies in CHF Patients

Summary

To determine if β-adrenergic blockade might inhibit the deleteriouseffects of the sympathetic nervous system on survival in heart failure(CHF), 1052 patients with CHF were prospectively enrolled into amulticenter trial program, in which patients were randomly assigned(double-blind) to 6-12 months' treatment with placebo (PBO) orcarvedilol (CRV),. After a common screening period, patients with classII-IV CHF (see next paragraph for the definitions of the classificationof CHF) and an ejection fraction ≦0.35 were assigned to one of fourprotocols based on performance on a 6-minute walk test. PBO or CRV wasadded to existing therapy with digoxin, diuretics and an ACE inhibitor.All-cause mortality was monitored by a prospectively constituted Dataand Safety Monitoring Board (DSMB). After 25 months of enrollment, theDSMB recommended termination of the program because of a favorableeffect of CRV on survival. By intention-to-treat, mortality was 8.2% inthe PBO group but only 2.9% in the CRV group (P=0.0001,Cochran-Mantel-Haensel analysis). This represented a reduction in riskof death by CRV of 67% (95% CI: 42% to 81%). The treatment effect wassimilar in patients with class II and class III-IV symptoms. Mortalitywas reduced in class II patients from 5.9% to 1.9%, a 68% reduction (95%CI: 20% to 97%) P=0.015,!, and in class III-IV patients from 11.0% to4.2%, a 67% reduction (95% CI: 30% to 84%), P=0.004, log-rank!.Importantly, the effect of CRV was similar in ischemic heart disease(risk reduced by 67%, P=0.003) and in non-ischemic dilatedcardiomyopathy (risk reduced by 67%, P=0.014). In conclusion, theaddition of CRV to conventional therapy is associated with a substantial(67%) reduction in the mortality of patients with chronic CHF. Thetreatment effect is seen across a broad range of severity and etiologyof disease.

As used herein, by "Class II CHF" is meant patients with cardiac diseaseresulting in slight or moderate limitation of physical activity. Theyare comfortable at rest. Ordinary physical activity results in fatigue,palpitations, dyspnea, or anginal pain. By "Class III CHF" is meantpatients with cardiac disease resulting in marked limitations ofphysical activity. They are comfortable at rest. Less than ordinaryphysical activity results in fatigue, palpitations, dyspnea, or anginalpain. By "Class IV CHF" is meant patients with cardiac disease resultingin inability to carry on any physical activity without discomfort,symptoms or cardiac insufficiency, or of the anginal syndrome. By "lessthan ordinary physical actvity" is meant climbing one flight of stairs,or walking two hundred yards.

Design of Study

Patients on background therapy with diuretics, ACE inhibitors and/ordigoxin were stratified on the basis of baseline submaximal exerciseperformance, into one of four trials:

study 220, a dose response study in moderate (NYHA II-IV) CHF withexercise testing as a primary endpoint

study 221, a dose titration study in moderate (NYHA II-IV) CHF withexercise testing as a primary endpoint

study 239, a dose titration study in severe (NYHA III-IV) CHF withquality of life as a primary endpoint

study 240, a dose titration study in mild (NYHA II-III) CHF withprogression of CHF as a primary endpoint

Sixty-four centers in the US participated in the trial program. Allsites conducted protocols 239 and 240, while 33 performed protocol 220and 31 performed protocol 221.

Although each trial had its own individual objectives, the overallprogram objective defined prospectively was evaluation of all-causemortality. Based upon a projected enrollment of 1100 patients, theprogram had 90% power to detect a 50% reduction in mortality (two-sided)between carvedilol and placebo, assuming a mortality rate in the placebogroup of 12% over the duration of the trials (α=0.05).

Randomization was preceded by a screening and challenge period common tothe four protocols The purpose of the screening period was to qualifypatients for study entry, obtain reproducible baseline measurements, andstratify patients into the appropriate trial based on submaximalexercise testing. During the challenge period, patients receivedlow-dose open-label carvedilol (6.25 mg b.i.d.) for two weeks. Patientsunable to tolerate this dose did not proceed to randomization. Patientstolerating low-dose carvedilol were then randomized to blindedmedication (carvedilol or placebo) with the dose titrated over severalweeks in the range of 6.25 to 50 mg b.i.d. (or equivalent level ofplacebo). The maintenance phase of each study ranged from six to 12months, after which patients had the option of receiving open-labelcarvedilol in an extension study.

Results

The analysis presented below corresponds to the data set on which theDSMB made the recommendation to terminate the trials. Included in thisintent-to-treat analysis are all patients enrolled in the U.S. trials asof Jan. 20, 1995; 624 receiving carvedilol and 356 placebo. An analysisof baseline patient characteristics (Table 1) shows good balance betweenthe randomized groups.

                  TABLE 1                                                         ______________________________________                                        US Carvedilol Heart Failure Trials - Baseline Characteristics                                    Placebo   Carvedilol                                       Characteristic     (n = 356) (n = 624)                                        ______________________________________                                        Age, mean ± SD (years)                                                                        59.9 ± 11.7                                                                          58.8 ± 11.8                                   Sex (% men)        62%       62%                                              Etiology (% ischemic)                                                                            43%       40%                                              Severity of CHF                                                               Class II           41%       41%                                              Class III-IV       40%       39%                                              Unknown            19%       20%                                              LV ejection fraction, mean ± SD                                                               0.22 ± 0.07                                                                          0.23 ± 0.08                                   6 Minute walk (m ± SD)                                                                        373 ± 88                                                                             379 ± 81                                      Blood pressure (mmHg)                                                                            115/73    115/73                                           Heart rate (bpm ± SD)                                                                         85 ± 13                                                                              86 ± 13                                       ______________________________________                                    

The overall mortality results for the program are shown in Table 2. Alldeaths that occurred during the intent-to-treat period are included.Treatment with carvedilol resulted in a 67% reduction in the risk ofall-cause mortality. Analysis of mortality by certain baselinecharacteristics shows this to be a broad effect regardless of severityor etiology of CHF. The effect was uniform in patients with mild heartfailure or moderate to severe heart failure. Similarly, the mortalityreduction was equivalent in patients with ischemic or non-ischemic heartfailure.

                  TABLE 2                                                         ______________________________________                                        Evaluation of Mortality in US Carvedilol CHF Studies                                                  Risk Reduction                                                 Carvedilol                                                                           Placebo (95% CI)   p value*                                   ______________________________________                                        All Cause Mortality                                                                      18/624   29/356  67%      <0.0001                                             (2.9%)   (8.2%)  (42-81)                                           Class II CHF                                                                              7/361   12/202  68%      0.015                                               (1.9%)   (5.9%)  (20-97)                                           Class III-IV CHF                                                                         11/263   17/154  66%      0.004                                               (4.2%)   (11.0%) (30-84)                                           Ischemic Etiology                                                                        10/311   16/178  67%      0.003                                               (3.2%)   (8.9%)  (32-85)                                           Non-Ischemic                                                                              8/313   13/178  67%      0.014                                    Etiology   (2.5%)   (7.3%)  (20-86)                                           ______________________________________                                         *Cochran-Mantel-Haensel Analysis                                         

Conclusion

The U.S. Phase III trials were prospectively designed to evaluate theeffects of carvedilol on the wellbeing and survival of patients withcongestive heart failure. Twenty-five months after the program wasinitiated, the independent Data and Safety Monitoring Board recommendedthat the trials be terminated because of a 67% reduction in all-causemortality. This effect was independent of the underlying severity oretiology of heart failure.

The foregoing is illustrative of the use of the compounds of thisinvention. This invention, however, is not limited to the preciseembodiment described herein, but encompasses all modifications withinthe scope of the claims which follow.

What is claimed is:
 1. A method of decreasing mortality caused bycongestive heart failure in a patient in need thereof which comprisesadministering a therapeutically acceptable amount of carvedilol inconjunction with one or more other therapeutic agents, said agents beingselected from the group consisting of an angiotensin converting enzymeinhibitor (ACE), a diuretic, and digoxin.
 2. A method according to claim1 which comprises administering carvedilol in a dosage range of fromabout 3.125 to about 50 mg given twice daily.
 3. A method according toclaim 1 which comprises administering carvedilol in a maintenance doseof about 25 mg given twice daily.
 4. A method according to claim 1 whichcomprises administering carvedilol in a maintenance dose of betweenabout 25 mg and about 50 mg given twice daily to patients whose weightexceeds about 85 kg.
 5. A method according to claim 1 which comprisesadministering carvedilol in a maintenance dose of about 50 mg giventwice daily in patients whose weight exceed about 85 kg.
 6. A methodaccording to claim 1 wherein said ACE inhibitor is captopril,lisinopril, or enalapril, or any pharmaceutically acceptable saltthereof.
 7. A method according to claim 1 wherein said diuretic ishydrochlorothiazide or furosemide, or any pharmaceutically acceptablesalt thereof.